IL271399B - שיטות להכנת תרכובות 3,1–בנזודיאוקסול הטרוציקליות - Google Patents
שיטות להכנת תרכובות 3,1–בנזודיאוקסול הטרוציקליותInfo
- Publication number
- IL271399B IL271399B IL271399A IL27139919A IL271399B IL 271399 B IL271399 B IL 271399B IL 271399 A IL271399 A IL 271399A IL 27139919 A IL27139919 A IL 27139919A IL 271399 B IL271399 B IL 271399B
- Authority
- IL
- Israel
- Prior art keywords
- compound
- formula
- mixture
- reaction
- dmf
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 72
- 238000002360 preparation method Methods 0.000 title claims description 21
- -1 heterocyclic 3,1-benzodioxole compounds Chemical class 0.000 title claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 156
- 239000000203 mixture Substances 0.000 claims description 106
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 77
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 43
- 239000011541 reaction mixture Substances 0.000 claims description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 21
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 21
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 20
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical group CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 18
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 125000001246 bromo group Chemical group Br* 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 11
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 11
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 claims description 11
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 10
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 8
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 6
- 239000004927 clay Substances 0.000 claims description 6
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 6
- 150000004692 metal hydroxides Chemical class 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000010457 zeolite Substances 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910021536 Zeolite Inorganic materials 0.000 claims description 5
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 5
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical group C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 claims description 3
- 239000011874 heated mixture Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- YKCQWIYRLMNGMO-UHFFFAOYSA-N 3,5-dichloro-1h-pyridin-4-one Chemical compound OC1=C(Cl)C=NC=C1Cl YKCQWIYRLMNGMO-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 2
- 235000011181 potassium carbonates Nutrition 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- ZICOPWJJZSJEDL-UHFFFAOYSA-N 3,5-dichloro-1h-pyridin-2-one Chemical compound OC1=NC=C(Cl)C=C1Cl ZICOPWJJZSJEDL-UHFFFAOYSA-N 0.000 claims 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 33
- 239000000047 product Substances 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 239000012071 phase Substances 0.000 description 28
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 19
- 239000003153 chemical reaction reagent Substances 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 238000013019 agitation Methods 0.000 description 16
- 239000008346 aqueous phase Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- 125000003003 spiro group Chemical group 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 210000002741 palatine tonsil Anatomy 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- QRADKVYIJIAENZ-UHFFFAOYSA-N 1-[[bromo(difluoro)methyl]-ethoxyphosphoryl]oxyethane Chemical compound CCOP(=O)(C(F)(F)Br)OCC QRADKVYIJIAENZ-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000004190 ion pair chromatography Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KKWRVUBDCJQHBZ-UHFFFAOYSA-N 3,4,5-trichloropyridine Chemical compound ClC1=CN=CC(Cl)=C1Cl KKWRVUBDCJQHBZ-UHFFFAOYSA-N 0.000 description 3
- ZSBNXOIAJFVXMP-UHFFFAOYSA-N 5-tert-butyl-2-methylbenzenethiol Chemical compound CC1=CC=C(C(C)(C)C)C=C1S ZSBNXOIAJFVXMP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 2
- OHMHBGPWCHTMQE-UHFFFAOYSA-N 2,2-dichloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)C(Cl)Cl OHMHBGPWCHTMQE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 150000003738 xylenes Chemical class 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 1
- 150000005529 1,3-benzodioxoles Chemical class 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- YAJYJWXEWKRTPO-UHFFFAOYSA-N 2,3,3,4,4,5-hexamethylhexane-2-thiol Chemical compound CC(C)C(C)(C)C(C)(C)C(C)(C)S YAJYJWXEWKRTPO-UHFFFAOYSA-N 0.000 description 1
- NHAUBUMQRJWWAT-UHFFFAOYSA-N 2,5-dimethylbenzenethiol Chemical compound CC1=CC=C(C)C(S)=C1 NHAUBUMQRJWWAT-UHFFFAOYSA-N 0.000 description 1
- MNOONJNILVDLSW-UHFFFAOYSA-N 2-chloro-2,2-difluoro-1-phenylethanone Chemical compound FC(F)(Cl)C(=O)C1=CC=CC=C1 MNOONJNILVDLSW-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- CESBAYSBPMVAEI-UHFFFAOYSA-N 3,5-dimethylbenzenethiol Chemical compound CC1=CC(C)=CC(S)=C1 CESBAYSBPMVAEI-UHFFFAOYSA-N 0.000 description 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- APDUDRFJNCIWAG-UHFFFAOYSA-N 4-propan-2-ylbenzenethiol Chemical compound CC(C)C1=CC=C(S)C=C1 APDUDRFJNCIWAG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- DZKIZVXCLNLUJF-UHFFFAOYSA-N [chloro(difluoro)methyl]sulfonylbenzene Chemical compound FC(F)(Cl)S(=O)(=O)C1=CC=CC=C1 DZKIZVXCLNLUJF-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- ORTRWBYBJVGVQC-UHFFFAOYSA-N hexadecane-1-thiol Chemical compound CCCCCCCCCCCCCCCCS ORTRWBYBJVGVQC-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- PWBJWDKDPAPGED-UHFFFAOYSA-N n'-chlorobutanediamide Chemical compound NC(=O)CCC(=O)NCl PWBJWDKDPAPGED-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- CAQKQIYWKXZJGD-UHFFFAOYSA-M sodium;2-bromo-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Br CAQKQIYWKXZJGD-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- GEKDEMKPCKTKEC-UHFFFAOYSA-N tetradecane-1-thiol Chemical compound CCCCCCCCCCCCCCS GEKDEMKPCKTKEC-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
- B01J21/16—Clays or other mineral silicates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17176767 | 2017-06-20 | ||
| PCT/EP2018/066229 WO2018234299A1 (en) | 2017-06-20 | 2018-06-19 | Methods for the preparation of 1,3-benzodioxole heterocyclic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL271399A IL271399A (he) | 2020-01-30 |
| IL271399B true IL271399B (he) | 2022-07-01 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL271399A IL271399B (he) | 2017-06-20 | 2018-06-19 | שיטות להכנת תרכובות 3,1–בנזודיאוקסול הטרוציקליות |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US11220514B2 (he) |
| EP (1) | EP3642210B1 (he) |
| JP (2) | JP2020524131A (he) |
| KR (1) | KR102676384B1 (he) |
| CN (2) | CN118344381A (he) |
| AU (1) | AU2018286964B2 (he) |
| BR (1) | BR112019025028A2 (he) |
| CA (1) | CA3064033A1 (he) |
| DK (1) | DK3642210T3 (he) |
| ES (1) | ES2998512T3 (he) |
| IL (1) | IL271399B (he) |
| MX (1) | MX394835B (he) |
| TW (1) | TWI774791B (he) |
| WO (1) | WO2018234299A1 (he) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11370799B2 (en) | 2015-12-18 | 2022-06-28 | UNION therapeutics A/S | Methods for the preparation of 1,3-benzodioxole heterocyclic compounds |
| BR112019025028A2 (pt) | 2017-06-20 | 2020-06-16 | Leo Pharma A/S | Método para preparar um composto. |
| JP7203846B2 (ja) | 2017-12-15 | 2023-01-13 | ユニオン・セラピューティクス・アクティエセルスカブ | 置換アゼチジンジヒドロチエノピリジンおよびホスホジエステラーゼ阻害剤としてのそれらの使用 |
| EP4282414A3 (en) | 2019-01-15 | 2024-02-21 | UNION therapeutics A/S | Modified release tablet formulations containing phosphodiesterase inhibitors |
| MX2023011176A (es) | 2021-03-22 | 2024-01-04 | Union Therapeutics As | Tratamiento de hidradenitis supurativa con orismilast. |
| CN114105865A (zh) * | 2021-12-07 | 2022-03-01 | 江苏宝众宝达药业股份有限公司 | 一种3,4,5-三氯吡啶的合成工艺 |
| GB202205715D0 (en) | 2022-04-19 | 2022-06-01 | Union Therapeutics As | Treatment of neutrophilic dermatoses |
| GB202306663D0 (en) | 2023-05-05 | 2023-06-21 | Union Therapeutics As | Combination therapy |
| GB202306662D0 (en) | 2023-05-05 | 2023-06-21 | Union Therapeutics As | Dosage regimen |
Family Cites Families (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03148337A (ja) | 1989-10-31 | 1991-06-25 | Aisin Seiki Co Ltd | ２輪／４輪駆動制御装置 |
| US6514996B2 (en) | 1995-05-19 | 2003-02-04 | Kyowa Hakko Kogyo Co., Ltd. | Derivatives of benzofuran or benzodioxole |
| DE69636086T2 (de) | 1995-05-19 | 2006-11-30 | Kyowa Hakko Kogyo Co., Ltd. | Sauerstoff enthaltende heterocyclische verbindungen |
| US6169086B1 (en) * | 1997-01-27 | 2001-01-02 | Daiichi Pharmaceutical Co., Ltd. | Pyrazole derivatives |
| JPH1159216A (ja) | 1997-08-26 | 1999-03-02 | Fuji Heavy Ind Ltd | ４輪駆動車の動力配分制御装置 |
| DE10049567B4 (de) | 1999-10-08 | 2017-12-14 | Toyota Jidosha Kabushiki Kaisha | Fahrzeugsteuergerät zum Steuern eines allradgetriebenen Kraftfahrzeugs |
| DE10205274A1 (de) | 2002-02-08 | 2003-08-21 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen enthaltend neben Anticholinergika heterocyclische Verbindungen |
| US6630813B2 (en) | 2002-03-06 | 2003-10-07 | Ford Global Technologies, Llc | Method and apparatus for monitoring the state of the battery of a hybrid electric vehicle |
| CA2491464A1 (en) | 2002-07-03 | 2004-01-15 | Kyowa Hakko Kogyo Co., Ltd. | Process for preparation of 1,3-benzodioxole-2-spiro- cycloalkane derivatives |
| US7771742B2 (en) | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
| JP2006008522A (ja) | 2004-06-22 | 2006-01-12 | Sumitomo Chemical Co Ltd | ２，３−ジヒドロキシ−４−アルコキシ−アシルベンゼン類の製造方法 |
| DE602007012105D1 (de) | 2006-07-14 | 2011-03-03 | Chiesi Farma Spa | Derivate von 1-phenyl-2-pyridinylalkylenalkohole als phosphodiesteraseinhibitoren |
| WO2008077404A1 (en) | 2006-12-22 | 2008-07-03 | Leo Pharma A/S | Substituted acetophenones useful as pde4 inhibitors |
| CA2676933C (en) * | 2007-02-28 | 2015-09-29 | Leo Pharma A/S | Novel phosphodiesterase inhibitors |
| HRP20160488T1 (hr) | 2008-12-19 | 2016-06-17 | Leo Pharma A/S | Triazolopiridini kao inhibitori fosfodiesteraze za liječenje kožnih bolesti |
| EP2555774B1 (de) | 2010-04-08 | 2015-10-21 | Boehringer Ingelheim International GmbH | Arnzeimittelkombinationen enthaltend pde4-inhibitoren und ep4-rezeptor-antagonisten |
| PT2585469T (pt) * | 2010-06-24 | 2016-08-29 | Leo Pharma As | Compostos heterocíclicos de benzodioxolo ou benzodioxepina como inibidores da fosfodiesterase |
| JP2012229192A (ja) | 2011-04-13 | 2012-11-22 | Jsr Corp | （ポリ）イソシアヌレート化合物の製造方法 |
| EP2794603B1 (en) | 2011-12-21 | 2016-06-15 | Leo Pharma A/S | [1,2,4]triazolopyridines and their use as phospodiesterase inhibitors |
| WO2014096018A1 (en) | 2012-12-19 | 2014-06-26 | Leo Pharma A/S | Methods for the preparation of substituted acetophenones |
| DK3157930T3 (en) * | 2014-06-23 | 2019-01-21 | Leo Pharma As | PROCEDURES FOR THE PREPARATION OF HETEROCYCLIC 1,3-BENZODIOXOL COMPOUNDS |
| US11370799B2 (en) * | 2015-12-18 | 2022-06-28 | UNION therapeutics A/S | Methods for the preparation of 1,3-benzodioxole heterocyclic compounds |
| RU2768746C2 (ru) | 2016-12-12 | 2022-03-24 | Юнион Терапьютикс А/С | Замещенные пиразолоазепин-4-оны и их применение в качестве ингибиторов фосфодиэстеразы |
| ES2874632T3 (es) | 2016-12-12 | 2021-11-05 | Union Therapeutics As | Pirazoloazepin-8-onas sustituidas y su uso como inhibidores de la fosfodiesterasa |
| RU2762279C2 (ru) | 2016-12-12 | 2021-12-17 | Юнион Терапьютикс А/С | Замещенные пиразолоазепин-4-оны и их применение в качестве ингибиторов фосфодиэстеразы |
| BR112019025028A2 (pt) | 2017-06-20 | 2020-06-16 | Leo Pharma A/S | Método para preparar um composto. |
| US11365204B2 (en) | 2017-09-20 | 2022-06-21 | UNION therapeutics A/S | Substituted dihydrothienopyrimidines and their use as phosphodiesterase inhibitors |
| US11292799B2 (en) | 2017-12-15 | 2022-04-05 | UNION therapeutics A/S | Substituted azetidine dihydrothienopyrimidines and their use as phosphodiesterase inhibitors |
| JP7203846B2 (ja) | 2017-12-15 | 2023-01-13 | ユニオン・セラピューティクス・アクティエセルスカブ | 置換アゼチジンジヒドロチエノピリジンおよびホスホジエステラーゼ阻害剤としてのそれらの使用 |
| US11299497B2 (en) | 2017-12-15 | 2022-04-12 | UNION therapeutics A/S | Substituted tetrahydropyran dihydrothienopyrimidines and their use as phosphodiesterase inhibitors |
| EP4282414A3 (en) | 2019-01-15 | 2024-02-21 | UNION therapeutics A/S | Modified release tablet formulations containing phosphodiesterase inhibitors |
| MX2023011176A (es) | 2021-03-22 | 2024-01-04 | Union Therapeutics As | Tratamiento de hidradenitis supurativa con orismilast. |
-
2018
- 2018-06-19 BR BR112019025028-0A patent/BR112019025028A2/pt active Search and Examination
- 2018-06-19 CA CA3064033A patent/CA3064033A1/en active Pending
- 2018-06-19 EP EP18730390.4A patent/EP3642210B1/en active Active
- 2018-06-19 ES ES18730390T patent/ES2998512T3/es active Active
- 2018-06-19 KR KR1020207001926A patent/KR102676384B1/ko active Active
- 2018-06-19 DK DK18730390.4T patent/DK3642210T3/da active
- 2018-06-19 JP JP2019565499A patent/JP2020524131A/ja not_active Ceased
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- 2018-06-19 AU AU2018286964A patent/AU2018286964B2/en active Active
- 2018-06-19 CN CN202410373395.3A patent/CN118344381A/zh active Pending
- 2018-06-19 WO PCT/EP2018/066229 patent/WO2018234299A1/en not_active Ceased
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- 2018-06-19 MX MX2019013979A patent/MX394835B/es unknown
- 2018-06-19 IL IL271399A patent/IL271399B/he unknown
- 2018-06-20 TW TW107121127A patent/TWI774791B/zh active
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2021
- 2021-12-01 US US17/539,715 patent/US12084457B2/en active Active
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2022
- 2022-11-22 JP JP2022186411A patent/JP7549635B2/ja active Active
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|---|---|
| CN118344381A (zh) | 2024-07-16 |
| JP2023029877A (ja) | 2023-03-07 |
| RU2019138518A (ru) | 2021-07-20 |
| TW201904975A (zh) | 2019-02-01 |
| ES2998512T3 (en) | 2025-02-20 |
| MX2019013979A (es) | 2020-07-13 |
| RU2019138518A3 (he) | 2022-04-14 |
| AU2018286964A1 (en) | 2019-12-05 |
| WO2018234299A1 (en) | 2018-12-27 |
| KR20200013784A (ko) | 2020-02-07 |
| EP3642210B1 (en) | 2024-11-13 |
| EP3642210A1 (en) | 2020-04-29 |
| CN110741005B (zh) | 2024-04-12 |
| JP7549635B2 (ja) | 2024-09-11 |
| US12084457B2 (en) | 2024-09-10 |
| US11220514B2 (en) | 2022-01-11 |
| AU2018286964B2 (en) | 2022-04-14 |
| CA3064033A1 (en) | 2018-12-27 |
| TWI774791B (zh) | 2022-08-21 |
| JP2020524131A (ja) | 2020-08-13 |
| US20210147440A1 (en) | 2021-05-20 |
| MX394835B (es) | 2025-03-24 |
| IL271399A (he) | 2020-01-30 |
| DK3642210T3 (da) | 2024-12-09 |
| BR112019025028A2 (pt) | 2020-06-16 |
| US20220162227A1 (en) | 2022-05-26 |
| KR102676384B1 (ko) | 2024-06-20 |
| CN110741005A (zh) | 2020-01-31 |
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